The blood glucose level is constantly controlled so as to fall within a certain range at a normal state. A peptide hormone called insulin is important for controlling the blood glucose level. This peptide hormone is excreted from β cells of islets of Langerhans present in the pancreas. When the insulin binds to an insulin receptor present on the cell membrane, various signal transductions occur to suppress gluconeogenesis, leading to a drop in the blood glucose level.
The reason why the blood glucose level is controlled is that glucose serves as a harmful substance causing glycosylation stress in tissue although it is a main energy source for organs including the brain.
When the control ability of the blood glucose level (glucose tolerance) is decreased, one is in a state where the blood glucose level has pathologically increased or a state where the blood glucose level potentially increases. Such a state that the glucose metabolism has been abnormal is diabetes.
The diabetes is classified into type 1 diabetes (insulin-dependent diabetes) and type 2 diabetes (insulin-independent diabetes). The type 2 diabetes, most of the diabetes belong to, is further classified into diabetes caused due to a decrease in the level of excreted insulin and diabetes in which although insulin is excreted at a sufficiently high level, the blood glucose level does not decrease due to reduction in insulin susceptibility of glucose in the target cells. The latter case is called insulin resistance.
The current diabetes therapy is conducted using various drugs selected depending on the pathological conditions. The types of the drugs are classified roughly into insulin, an insulin-excretion promoter, a glucose absorption inhibitor and an insulin resistance improving agent.
For patients exhibiting the above-described insulin resistance, an insulin resistance improving agent such as metformin hydrochloride, buformine hydrochloride or pioglitazone hydrochloride is used as the first-line drug. However, such an insulin resistance improving agent involves gastrointestinal disorder as side effects. In addition, it cannot be applied to those having a history of heart failure. Also, pioglitazone hydrochloride involves increase in body weight as side effects, which imposes problematic burden on patients who are receiving dietary therapy.
Meanwhile, besides insulin, signal transducer and activator of transcription 3 (STAT3) has recently been reported as a factor that decreases the blood glucose level (see Inoue H et al., Nat Med, 10(2), 2004, p. 168-74).
The STAT3 is a protein that works for both of signal transduction and transcription activation, and controls processes such as cell growth, differentiation and survival. The STAT3 exists in the cytoplasm in the non-phosphorylated form. When the STAT3 is activated by Janus kinase (JAK) so that its Tyr705 is phosphorylated, a homodimer of the STAT3 is formed and transferred into the nucleus, where it serves as a transcriptional factor to activate the target gene.
The homodimer of the STAT3 serves in the nucleus as an antagonist against a transcriptional factor responsible for gluconeogenesis. Increase in the expression level thereof suppresses gluconeogenesis to reduce the blood glucose level.
Also, as has been known, when Ser727 of the STAT3 is phosphorylated by extracellular signal-regulated kinase 2 (ERK2), formation of the homodimer of the STAT3 is inhibited (see Chung J et al., Mol Cell Biol, 17(11), 1997, p. 6508-16; Jain N et al., Oncogene, 17(24), 1998, p. 3157-67; and Liu S et al., Proc Natl Acad Sci USA, 103(14), 2006, p. 5326-31).
However, diabetes therapeutic drugs relating to the STAT3 have not been known.
Thus, in the prevention or therapy for diabetes, there have not yet been provided an effective, safe drug having a target molecule and mechanism which are different from those of these existing drugs; and an efficient screening method for a candidate substance of the above drug. At present, keen demand has arisen for the provision of them.